Mucosal bioadhesive slow release carrier for delivering active principles

ABSTRACT

A mucosal bioadhesive slow release carrier comprising an active principle and devoid of starch, lactose, which can release the active principal for a duration of longer than 20 hours. This bioadhesive carrier contains a diluent, an alkali metal alkylsulfate, a binding agent, at least one bioadhesive polymer and at least one sustained release polymer, as well as a method for its preparation.

1. FIELD OF THE INVENTION

The present invention relates to a bioadhesive slow release carrier forthe extended and controlled release of an active principle that can beused on mucosal surfaces. A process for manufacturing the bioadhesivesystem, a method for delivering an active ingredient to a mammal, aswell as methods of treating, curing or preventing various medicalconditions are also disclosed.

2. BACKGROUND OF THE INVENTION AND RELATED PRIOR ART

Mucous membranes are linings of ectodermic origin, covered inepithelium, and are involved in absorption and secretion. They linevarious body cavities that are exposed to the external environment aswell as internal organs, such as the nostrils, the lips, the ears, thegenital area, the digestive tract and the anus. Parts of the bodyfeaturing mucous membranes include most of the respiratory tract and theentire gastrointestinal tract, as well as the vagina, cervix, theclitoris, the covering of the glans penis and the inside of the prepuce.Many of the afore mentioned mucous membranes secrete mucus, which is aviscous colloid containing antiseptic enzymes such as lysozymes andimmunoglobulins and is made up of mucins and inorganic salts suspendedin water.

One of the problems associated with a bioadhesive drug delivery systemfor mucous membranes is that the lubricious nature of the mucousmembranes allows for the active substance to be washed away or dilutedlowering the drugs bioavailability such that the administered drug doesnot effectively treat the medical condition at hand. Another problem isthat in the oral cavity, eating drinking and speaking and the constantreplacement of the saliva often effects the delivery of the activesubstance.

Oral mucosa bioadhesive delivery systems are also well known in the artand are used to treat various medical conditions. These delivery systemsare generally made of water soluble carbomers or insoluble polymers thatcan contain maize starch as a disintegrating agent and/or lactose as adiluent or binder. Generally the delivery of the active principle isover a period of less than 11 hours. Thus, in these drug deliverysystems the carrier has to be replaced at least twice a day.

For instance, U.S. Pat. No. 5,643,603 describes a composition of abioadhesive sustained delivery carrier for drug administration, whichcomposition is made up of a mixture of pregalatinized starch and asynthetic polymer such as polyacrylic acid, hydroxyethyl cellulose,carboxymethyl cellulose, PVA, PVP and PEG (95%) and a drug (0.1 to 5%).This bioadhesive can be adhered to the mucosa or teeth and was deemed todeliver the drug over a period of seven hours.

Another form of a bioadhesive tablet is described in U.S. Pat. No.6,248,358 in which the active ingredient is protected from water and thesurrounding environment. This tablet contains 5 to 50% by weighthydroxypropyl methyl cellulose, 0.5 to 25% by weight corn starch, 1 to50% by weight lactose, 0.5 to 10% by weight water insoluble cross-linkedpolycarbophil and 1 to 75% by weight carbomer or carbomer 974P. Thishydrated sustained release tablet can deliver the active ingredient tothe bloodstream via the patients vaginal or buccal cavity.

A bioadhesive solid dosage form is described in U.S. Pat. No. 6,303,147,which has 0.001 to 10% of an active ingredient, 80 to 98% ofpregelatinized starch, 1 to 10% of a hydrophilic matrix forming polymersuch as polyacrylic acid, carbomer, hydroxyethyl cellulose, HPMC,carboxymethylcellulose, PVA or mixtures of these hydrophilic polymers,0.2 to 5% of sodium stearyl fumarate and 0 to 1% of a glidant. it can beused for buccal, nasal, rectal or vaginal administration. The adhesiontime of these tablets is about nine hours.

U.S. Pat. No. 6,916,485 describes a prolonged release bioadhesivetherapeutic system containing 10 to 2,000 mg active ingredient, 50% byweight natural proteins, at least 20% by weight of milk proteinconcentrate, 10 to 20% by weight of a hydrophilic polymer, a compressionexcipient such as corn starch, lactose or polyol and 3.5 to 10% byweight alkali metal alkylsulfate. This system is a mucoadhesive tabletfor delivery to the mucosa.

All of the above issued patents use corn starch as a disintegratingagent or agents which plays a role in the prolonged release of theactive ingredient. Also all of these patents disclose the use of lactoseas a diluent or as a binding agent in their formulations. U.S. Pat. Nos.5,643,603, 6,303,147 and 6,916,485 disclose the delivery of the activeprinciple between 7 to 13 hours.

However, many people are lactose intolerant or are allergic to corn.Therefore, mucosal delivery systems containing lactose or corn areimpossible to use by this population of people.

Moreover, in many of the above-mentioned slow release bioadhesivesystems, the formulation of low aqueous soluble or insoluble activeprinciples is difficult. Various categories of medicinal agents such asantivirals, analgesics, anti-inflammatories, antibiotics and antisepticshave members, which are hard to formulate and administer due to theirlow aqueous solubility or insolubility. An example of an antiseptic withlow aqueous solubility is iodine, which crystallizes when placed inwater. Another example of an insoluble analgesic that is difficult toformulate is fentanyl base. Numerous antiviral and immunosuppressiveagents such as acyclovir are also difficult to formulate, have poorpercutaneous penetration and have complications arising due tointramuscular administration at a strongly alkaline pH of 10-11.

For instance, the oral absorption of acyclovir is highly variable with abioavailability ranging from 15% and 30%. In patients the systemictreatment regimen is 200 mg tablets, five times a day. Moreover, aftersystemic administration of acyclovir orally, peak acyclovirconcentrations are found in saliva at the lower end of the 50%inhibitory dose of herpes simplex-1 virus. Local treatment of acycloviras a cream is also poor due to poor percutaneous absorption. This creammust be applied at least 5 times a day over a period of 5 days.

Patients being treated for malignant diseases or HIV have further oralcomplications associated with their particular disease, due toimmunosuppression. For instance, some of the most common oralmanifestations in people who are infected with AIDS include bacterialinfections such as gingivo-periodontal disease, fungal infections suchas Candidiasis, viral infections such as Epstein-Barr virus, oral hairyleukoplakia, herpes simplex-1 virus, variacella-Zoster virus, humanpapilloma virus, cytomegalovirus, neoplasms such as Kaposi's sarcoma andlymphoma and other oral lesions including oral ulcers and salivary glandenlargement. Oral pain may be associated with each one of thesecomplications.

Likewise, people undergoing chemotherapy and head/neck radiation alsohave oral complications including mucositis, infection, salivary glanddysfunction, taste dysfunction, viral, fungal and bacterial infections,xerostomia and gastrointestinal mucositis caused by the secondarymodifications in the oral cavity. In about 40% of patients undergoingchemotherapy ulcerative oral mucositis occurs. In patients undergoingneck irradiation ulcerative oral mucositis occurs in almost every case.

Therefore, there is a need to accommodate multiple drugs treatingdifferent medical complications in a single drug delivery system toavoid multiple administration of different medicaments.

Furthermore, when many of the drugs are administered to treat the oralcomplications, they have to be administered very frequently since theyare generally released from the bioadhesive delivery system over aperiod of time from about 7 to 13 hours. The bioadhesive delivery systemthus has to be changed frequently, which can result in added burden tothe mammal receiving such treatment.

Thus, there are problems associated in the prior art for mucosaldelivery that can deliver the active principle to treat various medicalcomplications over a long period of time and more specifically greaterthan 20 hours. Furthermore there are problems also associated with theprior art with respect to the delivery of active principles, which havelow aqueous solubility or are insoluble. Moreover, there is a need inthe art to diminish taking multiple drugs to treat different medicalconditions.

Therefore it is an object of the present invention to overcome thedeficiencies in the prior art bioadhesive delivery systems.

It is an object of the present invention to provide a bioadhesive slowrelease carrier for mucosal delivery of an active ingredient for atleast 20 hours duration.

It is another object of the present invention to provide a bioadhesiveslow release carrier for mucosal delivery of a soluble or insolubleactive principle.

It is yet another object of the present invention to provide a mucosaldelivery bioadhesive slow release carrier in which the active principlecan be administered once a day.

Another object if the present invention is to provide a mucosalbioadhesive slow release carrier in which the active principle can beliberated immediately and then liberated over a prolonged period of timeof greater than 20 hours.

It is yet another object of the present invention to provide a mucosalbioadhesive slow release carrier that can contain at least two differentactive principles.

It is yet another object of the present invention to provide a processfor manufacturing a mucosal bioadhesive slow release carrier withoutlactose or corn starch.

It is another object of the present invention to provide a process formanufacturing a mucosal bioadhesive slow release carrier that candeliver a soluble or insoluble active principle.

Yet another object of the present invention is a method for deliveringan active principle to a mammal, especially mammals that areimmunodepressed.

Methods of treating, curing or preventing various medical conditions anddiseases are also objects of the present invention.

Methods of treating, curing or preventing mucosal diseases such asbuccal diseases are also objects of the present invention.

Use of the mucosal bioadhesive slow release carrier for the manufactureof medicaments to treat, cure or prevent certain diseases is also anobject of the present invention.

These and other objects are achieved by the present invention asevidenced by the summary of the invention, description of the preferredembodiments and the claims.

SUMMARY OF THE INVENTION

The present invention provides a mucosal bioadhesive slow release canercomprising a wetting agent comprising at least one active principlecomprising 1 to 75% by weight of a diluent, and 1 to 10% by weight of analkali metal alkylsulfate, and further comprising 0.5 to 5% by weight ofa binding agent and 5 to 80% by weight of at least one bioadhesivepolymer selected from the group of natural polymers wherein said naturalpolymers are polysaccharides or, natural proteins from animal origin orvegetable origin or synthetic polymers, and mixtures thereof and 5% to80% by weight of at least one polymer that provides a sustained releaseof the active principle.

The at least one polysaccharide that can be used in the presentinvention include chitosan, alginate, carboxymethyl cellulose,hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose, cyclodextrin, sodium hyaluronate and xanthum gum.

The at least one natural protein from vegetable origin or animal originthat can be used in the present invention include natural milk protein,natural pea protein, natural soy protein, natural potato protein,natural wheat protein and gliadin protein.

The at least one synthetic polymer that can be used in the presentinvention include carbomer, polyvinylalcohol and acrylic polymers.

The at least one active principle that can be used in the presentinvention include analgesics, anaesthetics such as lidocain, antalgics,antiviral agents, anti-inflammatory agents, antiemetic agents,antibiotics and antiseptics. Two or more different active principlesbesides the ones mentioned above including antiviral agents withdifferent spectrum than those described above, an antifungal agent and asalivary agent can also be formulated in the bioadhesive carrier of thepresent invention.

In another aspect the present invention also provides a method forpreparing a mucosal bioadhesive slow release carrier comprising:

-   a) granulating a mixture of at least one active principle with an    alkali metal alkylsulfate, a diluent and a binding agent;-   b) blending said granulated mixture with at least one bioadhesive    polymer, at least one sustained release polymer and at least one    compression agent; and-   c) compressing the blended mixture obtained in b).

In yet another aspect the present invention provides a method fordelivering an active principle to a mammal, said method comprisingmucosally administering to a mammal in need of said active principle, abioadhesive slow release carrier comprising a wetting agent comprisingat least one active principle, 1 to 75% by weight of a diluent and 1 to10% by weight of an alkali metal alkylsulfate and further comprising 0.5to 5% by weight of a binding agent and 5 to 80% by weight of at leastone bioadhesive polymer selected from the group of natural polymerswherein said natural polymers are polysaccharides or, natural proteinsfrom animal origin or vegetable origin or synthetic polymers, andmixtures thereof and 5 to 80% by weight of at least one polymer thatprovides a sustained release of the active principle.

Methods of alleviating, treating, preventing or curing various medicalconditions also are a part of the present invention. Thus, medicalconditions or diseases such as orofacial herpes-herpes simplex virus 1(HSV-1), genital herpes-herpes simplex virus 2 (HSV-2), oral mucositis,fungal infections such as Candidiasis, viral infections such asEpstein-Barr virus, oral hairy leukoplakia, variacella-Zoster virus,human papilloma virus, cytomegalovirus, Kaposi's sarcoma due to humanherpes V8 and genital warts due to human papilloma virus and other orallesions including oral ulcers and salivary gland disturbance, alteredoral flora (decreased bacterial flora), taste dysfunction,periodontitis, xerostomia (salivary gland dysfunction), gastrointestinalmucositis causing secondary changes in oral status includinginflammation, hygiene and dietary intact and oral pain can be treatedusing the mucosal bioadhesive slow release carrier of the presentinvention.

The methods of alleviating, treating, preventing or curing the abovemedical conditions using the mucosal bioadhesive slow release carrier ofthe present invention can be used to treat immunocompromised mammals.

Use of the mucosal bioadhesive slow release carrier of the presentinvention for the manufacture of a medicament to alleviate, treat,prevent or cure mucosal diseases or buccal diseases or genital diseasesis also provided in the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic representation of the process of the presentinvention.

FIG. 2 is graph showing the diameter of mesh of the graded sizesobtained from the formulation of the present invention compared to theformulation described in U.S. Pat. No. 6,916,485.

FIG. 3 is a graph showing the dissolution of acyclovir from thebioadhesive slow release carrier of the present invention over time inhours. 50 mg and 100 mg dosages were used.

FIG. 4 is a graph showing the concentration acyclovir in the plasma overtime in hours using the bioadhesive slow release carrier of the presentinvention compared with that of an oral acyclovir tablet.

FIG. 5 is a graph showing the concentration of acyclovir in the salivaover time in hours using the bioadhesive slow release carrier of thepresent invention compared with that of an oral acyclovir tablet.

FIG. 6 is a graph showing the concentration of acyclovir on the lipsover time in hours using the bioadhesive slow release carrier of thepresent invention compared with that of an oral acyclovir tablet.

FIG. 7 is a graph showing the adhesion force of the bioadhesive slowrelease carrier of the present invention using different bioadhesiveagents.

DESCRIPTION OF THE PREFERRED EMBODIMENTS OF THE INVENTION

As used herein the term “mucosal” encompasses oral/buccal, vaginal,esophageal, nasal and rectal delivery.

The term “bioadhesive” refers to any adhesive that interfaces withliving tissue and/or biological fluid.

By the term “carrier” is meant any object that can transport at leastone active principle.

As used herein the term “active principle”, “drug” and “activeingredient” are used interchangeably. The active principle is used toalleviate, treat or prevent a medical condition or disease. In someinstances the active principle can be used to cure a medical conditionor disease.

“Medical condition” and “disease” are also used interchangeably hereinand refer to any condition in a mammal or one of its parts that impairsnormal functioning in the mammal. This impairment may lead to illness orsickness characterized by certain symptoms and physical findingssuffered by a mammal.

The term “mammal” encompasses any of various warm-blooded vertebrateanimals of the class Mammalia, including humans, characterized by acovering of hair on the skin and, in the female, milk-producing mammaryglands for nourishing the young.

As used herein the term “buccal” means of, relating to, involving orlying in the mouth.

As used herein the term “diluent” means a diluting agent and encompassessuch agents that are insoluble diluents and soluble diluents.

The term “binder” when used herein relates to any pharmaceuticallyacceptable film which can be used to bind together the active and inertcomponents of the carrier together to maintain cohesive and discreteportions. Binders provide the matrix from which the active principle isgradually secreted.

As used herein, the expression “residence time” will refer to the timefor which the carrier placed on the target mucosal surface will remainsubstantially intact.

Similarly, throughout the text, the expression “slow release” or“sustained release” are used interchangeably and mean that the activeprinciple is released immediately after 30 minutes and then over aprolonged period of time of at least 15 hours or at least 18 hours or atleast 20 hours or at least 24 hours and up to 36 hours.

By the term “insoluble” when referring to the active principle meansthat the drug can be totally insoluble in an aqueous medium or haslimited solubility in an aqueous medium.

By “limited solubility” is meant that the active principle has asolubility below 10 mg/ml in 250 ml of water over a pH range from 1.0 to7.5. Classes of drugs that can have “limited solubility” are those drugsthat are hydrophobic or those which are classified in theBiopharmaceutical Classification System (BCS) as being type III or typeIV drugs.

More specifically, the present invention relates to a mucosalbioadhesive slow release carrier that can deliver an active principleover a period of time of at least 20 hours and up to 36 hours. Morespecifically the active principle can be delivered from 30 minutes to 15hours, 30 minutes to 18 hours, 30 minutes to 20 hours or 30 minutes to24 hours or 30 minutes to 36 hours. Thus, this carrier has the advantagethat it provides an effective residence time for the active principlesuch that only a single daily dosage is necessary.

Moreover, due to its increased bioavailability of the active principle,a reduced dosage of active principle is feasible using this drugdelivery system since, as evidenced in the Examples, the delivery of theactive principle is higher than the minimum inhibitory concentrationover a prolonged period of time.

More specifically, the bioadhesive slow release carrier of the inventioncan be used for preventing, alleviating, curing or treating mucosaldiseases, buccal, oesophageal or vaginal infections in mammals.

Still more specifically, bioadhesive slow release carrier of theinvention can be used for preventing, alleviating, curing or treatingbuccal herpes simplex 1 (HSV-1) infections, especially inimmunodepressed mammals such as those mammals that have AIDS or SIV orhave been subjected to chemotherapy or radiation therapy.

The present invention is not limited to treating only humans, but alsoencompasses veterinary applications, especially since it is well knownthat animals also can have oral medical complications.

The process to formulate the bioadhesive slow release carrier of thepresent invention permits the use of an active principle, which can besoluble, insoluble or having limited solubility in an aqueous solutionsuch as water. It is known in the art that insoluble or limitedsolubility drugs pose problems in their formulation and there is limitedchoice for a delivery system. In many delivery systems there isdecreased bioavailability of the active principle, incomplete releasefrom the dosage form and higher interpatient variation. Thus, in manyinstances the active principle must administered more frequently andmonitored more closely. The present invention overcomes thesedifficulties.

The carrier of the present invention can be in the form of a tablet,microspheres and the like. They can be formulated in any shape such asrectangular, circular, square, oval and the like. It should beappreciated that the dimensions of the carrier depend on the deliverymode that is used. For example, for gingival delivery, the carrier has aflat surface and a curved surface. The carrier can also be coated withan active principle described hereafter.

The mucosal bioadhesive slow release carrier of the present inventioncomprises at least one active principle, a diluent, an alkali metalalkylsulfate, a binding agent, at least one bioadhesive polymer and atleast one polymer that provides sustained release of the activeprinciple.

More specifically, mucosal bioadhesive slow release carrier comprises awetting agent comprising at least one active principle, 1 to 75% byweight of a diluent and 1 to 10% by weight of an alkali metalalkylsulfate and further comprising 0.5 to 5% by weight of a bindingagent and 5 to 80% by weight of at least one bioadhesive polymerselected from the group of natural polymers wherein said naturalpolymers are polysaccharides or natural proteins from animal origin orvegetable origin or synthetic polymers and mixtures thereof and 5% to80% by weight of at least one polymer that provides a sustained releaseof the active principle.

The at least one polysaccharides that can be used in the presentinvention include for example chitosan, alginate, carboxymethylcellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose,hydroxypropyl cellulose, sodium hyaluronate, cyclodextrin and xanthumgum.

The at least one natural protein from vegetable origin or animal originthat can be used in the present invention include natural milk protein,natural pea protein, natural soy protein, natural potato protein,natural wheat protein and gliadin protein.

The at least one synthetic polymer that can be used in the presentinvention include carbomer, polyvinylalcohol and acrylic polymers.

More specifically, the active principle which is incorporated into thebioadhesive slow release carrier includes antiviral agents, antifungals,analgesics, anaesthetics, antalgics, anti-inflammatory agents,antiemetics, antibiotics and antiseptics. More than one active principlecan be used depending on the needed application. For example, one canenvision treating herpes simplex 1 using an antiviral such as acyclovir,as well as an anti-inflammatory for pain in the same bioadhesivecarrier.

Examples of antiviral agents that can be used in the bioadhesive carrierinclude, for example, vidarbine, acyclovir, ganciclovir, cidovir,valganciclovir, nucleoside analog reverse transcriptase inhibitors suchas zidovudine, didanosine, zalcitabine, stavudine, lamivudine,non-nucleoside reverse transcriptase inhibitors such as nevirapine anddelavridine, protease inhibitors such as saquinavir, ritonavir,indinavir, nelfinavir, ribavirin, amantadine, rimantadine, releenza,tamiflu, pleconatil, penciclovir, famciclovir, foscamet, interferonssuch as IFN-α and the like.

The antiviral agent is present in the bioadhesive carrier in aconcentration between 10 to 200 mg. It can also be present in aconcentration between 50 to 100 mg. It will be appreciated that theamount of the antiviral can vary depending on the mammal being treatedas well as the medical condition of the mammal.

Examples of antifungal agents that can be used in the bioadhesivecarrier include, for example, polyene antimycotic and imidazole andtriazole such as clotrimazole.

The dosage of antifungal varies in the bioadhesive carrier with theantifungal utilized. Generally the does is between 10 mg to 150 mg.

Sulfa drugs and folic acid analogs, the beta-lactams includingpenicillins, vancomycin, ampicillin and amoxicillins and cephalosporins,aminoglycosides such as streptomycin, kanamycin, neomycin andgentamycin, tetracyclines such as doxycycline, macrolides, licosamides,streptogramins, fluoroquinolines such as ciprofloxacin, levofloxacin andmoxifloxacin, polymixins, rifampin, mupirocin, cycloserine,aminocyclitols, glycopeptides and oxazolidinones are examples ofantibiotics that can be used in the bioadhesive slow release carrier.

The dosage of antibiotic varies in the bioadhesive carrier with theantibiotic utilized. Generally the does is between 10 mg to 150 mg.

Examples of anti-inflammatory drugs that can be used in the bioadhesivecarrier include aspirin, salsalate, diflunisal, ibuprofen, ketoprofen,nabumetone, piroxicam, naproxen, diclofenac, indomethacin, sulindac,tolmetin, etodolac, ketorolac, oxaprozin, trisalicylate, acetaminophen,suprofen, corticoids, celecoxib and thalidomide.

The dose of the anti-inflammatory present in the bioadhesive slowrelease carrier is between 25 and 1,500 mg or between 50 and 500 mgdepending on the anti-inflammatory utilized.

Sodium laurylsulfate, iodophore, iodine, chlorhexidine gluconate,quaternary ammonium compounds such as cetylpyridinium chloride, phenolicantiseptics such as Listerine®, povidone-iodine, hexetidine, triclosan,delmopinol, salifluor, sanguinarine, alkali metal akylsulfates andpropolis are antiseptics that can be used in the present invention.

Between 0 to 5% of the antiseptic is used in the bioadhesive carrier ofthe invention.

Antiemetic drugs that can be used to treat nausea and vomiting,especially after chemotherapy include granisetron, ondansetron,dexamethasone and metoclopramide, 5-hydroxytryptanine (serotonin)inhibitors, dronabinol and prochloperazine and tropisetron. These drugsand combinations thereof can be used in the bioadhesive carrier.

The antiemetic is generally present in a dose between 1 to 100 mg in thecarrier.

Besides the active principle, the bioadhesive slow release carrier hasan adhesive system, which allows the carrier to adhere to mucosalsurfaces over a prolonged period of time. The adhesive system comprisesa diluent, an alkali metal alkysulfate, a binding agent, at least onebioadhesive polymer and at least one sustained release polymer.

The diluent used in the present invention can be insoluble or soluble.The diluent used is insoluble when the active principle is soluble andthe diluent is soluble when the active principle is insoluble.

Examples of insoluble diluents include microcrystalline cellulose,silicified microcrystalline cellulose, hydroxymethylcellulose, dicalciumphosphate, calcium carbonate, calcium sulfate, magnesium carbonate,tricalcium phosphate and the like.

Examples of soluble diluents include mannitol, glucose, sorbitol,maltose dextrates, dextrins, dextrose and the like.

The diluent is present in an amount between 1 and 75% by weight in thebioadhesive slow release carrier.

An alkali metal alkylsulfate is also a component of the bioadhesivecarrier of the present invention. This alkali metal sulfate increasesthe granulation of the active principle acting as a solubilizationagent. The alkali metal alkylsulfate that can be used in the formulationincludes magnesium lauryl sulfate, potassium lauryl sulfate, sodiumlaurylsulfate and diethylsulphosuccinate. Generally it is present in thebioadhesive carrier at a concentration of between 1 to 10% by weight or2 to 10% by weight.

The mucosal bioadhesive slow release carrier used in the presentinvention permits the immediate local liberation of the activeprinciple, as well as the prolonged liberation of the active principle.

The binders used in the present invention can be selected from carboxyvinyl polymer, methycellulose, hydroxyethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polyethylene glycol and the like. Thebinders are present in the amount of 0.5 to 5% by weight in thebioadhesive slow release carrier.

The bioadhesive polymers are selected from the group of naturalpolymers, polysaccharides, chitosan, alginate, carboxymethyl cellulose,hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose, cyclodextrin, sodium hyaluronate, xanthum gum, naturalproteins from animal origin or vegetable origin, natural milk proteins,natural pea proteins, natural soy proteins, natural potato proteins,natural wheat proteins, gliadin proteins, synthetic polymers, carbomer,polyvinylalcohol, acrylic polymers and mixtures thereof.

They are present in the bioadhesive carrier at a concentration of 5 to80% by weight. The can also be present in an amount of 10% to 40% byweight.

Regarding the natural milk proteins, these are described in EP 0 542824. They can be obtained from pasteurized raw milk and include totalmilk proteins, casein protein concentrates and whey proteinconcentrates.

The total milk proteins are recovered from skimmed milk afterultrafiltration. The casein protein products are obtained byinsolubilizing the casein in milk at its isoelectric point, and furtherwashing and drying the casein. The whey protein concentrates areobtained after coagulating cheese with enzymes and separating theyellow-green liquid residue out, which residue is whey. The whey is thenfurther concentrated by ultrafiltration, ion exchange chromatography orthermal precipitation.

Example of milk proteins are those titrating a minimum of 85% proteinssuch as Prosobel L85, 1180, 1380 or 1395 or Promilk852A sold by ArmorProteins or from the Alaplex range (4850, 1180, 1380 or 1395) from NZMP(Paris, France).

Regarding the vegetable proteins, they can be obtained from pea, soy,potato, wheat or gliadin. The method for producing pea protein isdescribed in WO 2007/017571.

Example of pea proteins are those titrating a minimum of 85% proteinssuch as Nutralys® sold by Roquette (France).

The sustained release polymers that can be used in the bioadhesivecarrier include hydrophilic polymers including polysaccharides such ascellulose ethers, xanthum gum, scleroglucan, locust bean gum, gumArabic, gum tragacanth, carob, alginic acid, alginates, carrageenates,agar-agar and guar gum either alone or in mixtures thereof. Otherpolymers that can be used in the present invention include cellulosebased polymers such as hydromellose, cellulose acetate, celluloseesters, cellobiose, cellulose resins alone or in mixtures thereof.

The sustained release polymers are present in a concentration of 5% to80% by weight. They can also be present in an amount of 10% to 40% byweight.

The alkali metal alkylsulfate is present in a concentration of 1 to 10%by weight. They can also be present in an amount of 2% to 6% by weight.

Salivation agents such as pilocarpin and bethanechol and flavoringsagents can also be added. Flavoring agents include calcium citrate,Safrole, and sweetening agents such as aspartame, cyclamates, saccharinand xylitol. Additionally compression excipients such as flow aidsincluding talc, colloidal silicone dioxide, colloidal silica andlubricants including magnesium stearate, stearic acid, polyethyleneglycol can also be added to the bioadhesive slow release carrier at thestage of blending.

These additional agents can be added to the carrier in the concentrationrange of 0.1 to 10% by weight of the total weight of the components inthe carrier.

In one embodiment the bioadhesive slow release carriers are intended toprevent and treat HSV-1, HSV-2, varicella zoster virus (VZV),Epstein-Barr virus, human herpes virus 8, avian influenza, mumps, HIV,respiratory syncitial virus, influenza, parainfluenza andcytomegalovirus infections. A preferred active principle is a compoundfrom the spectrum of nucleosides antivirals preferably selected fromacyclovir, valacyclovir, ganciclovir or zidovudine. Thus in one aspectthe nucleoside antiviral compound used in the bioadhesive is acyclovir,present in a dose of 10 to 200 mg per carrier.

In yet another embodiment the present invention relates to a mucosalbioadhesive slow release carrier comprising a wetting agent comprising10 to 200 mg of an antiviral agent selected from the group of acyclovir,valacyclovir, gancyclovir and zidovudine, 1 to 75% by weight of adiluent of microcrystalline cellulose and 2 to 10% by weight of sodiumlauryl sulphate and further comprising 0.5 to 5% by weight of apolyvinylpyrrolidine and 10 to 40% by weight of at least one bioadhesivepolymer selected from the group of natural milk proteins and mixturesthereof and 10% to 40% by weight of hypromellose.

In addition, and especially in the case of treating two differentmedical conditions the active principle described above can be combinedwith an antiviral, an antifungal, an analgesic, an anaesthetic, anantalgic, an antiemetic, a salivation agent, an antiseptic, ananti-inflammatory, an antibiotic and mixtures thereof.

For example, if a patient has herpes simplex virus 1 and pain thecombined use of acyclovir with an analgesic such as ibuprofen isparticularly advantageous since HSV-1 infection is sometimes accompaniedby labial or buccal pain.

Thus, the present invention provides a mucosal bioadhesive slow releasecarrier comprising a wetting agent comprising at least two activeprinciples selected from the group of antiviral agents, analgesics,anaesthetics, antalgics, anti-inflammatory antiemetics, antibiotics,antiseptics, an antiviral, an antifungal, a salivation agent, 1 to 75%by weight of a diluent and 1 to 10% by weight of an alkali metalalkylsulfate and further comprising 0.5 to 5% by weight of a bindingagent and 5 to 80% by weight of at least one bioadhesive polymerselected from the group of natural polymers wherein said naturalpolymers are polysaccharides or natural proteins from animal origin orvegetable origin or synthetic polymers, and mixtures thereof and 5% to80% by weight of at least one polymer that provides a sustained releaseof the active principle.

The combination of at least two active principles is also important intreating oral complications that arise from chemotherapy and head andneck radiation due to direct lethal and sublethal damage to oraltissues. Moreover, many patients have decreased immune systems, whichlead to problems in the healing of oral tissues. Thus complicationsarising with patients undergoing chemotherapy and radiation treatmentinclude oral mucositis, oral viral, bacterial and fungal infections,salivary gland dysfunctions altered oral flora, taste dysfunctions,xerostomia and gastrointestinal mucositis, which causes secondarychanges in oral status including taste, hygiene and dietary intact.Gastrointestinal mucositis causes nausea and vomiting. Thesecomplications require treatment with more than one drug. For example,one can use the analgesic fentanyl base, fentanyl citrate or sulfentanylwhich are important in treating severe resistant pain in particularassociated with cancer, and an antiemetic to treat nausea and vomiting.It will be appreciated that the combinations of the different activeprinciples utilized are based on the medical conditions that thepatient/mammal has and the treatment that is necessary.

Hence the present invention provides a bioadhesive slow release carrierthat can be used in the treatment of oral complications due tochemotherapy or radiation treatment comprising a wetting agentcontaining at least two active ingredients selected from the group ofantiviral agents, analgesics, anaesthetics, antalgics, anti-inflammatoryagents, antiemetics, antibiotics, antiseptics, an antiviral, anantifungal, a salivation agent, 1 to 75% by weight of a diluent and 1 to10% by weight of an alkali metal alkylsulfate and further comprising 0.5to 5% by weight of a binding agent and 5 to 80% by weight of at leastone bioadhesive polymer selected from the group of natural polymerswherein said natural polymers are polysaccharides or natural proteinsfrom animal origin or vegetable origin or synthetic polymers, andmixtures thereof and 5% to 80% by weight of at least one polymer thatprovides a sustained release of the active principle.

The unique properties of the mucosal bioadhesive slow release carrier isdue to its formulation. Generally the process of the present inventionconcerns using a wet granulation technique in its formulation.

In the methods of the prior art there is generally a wetting agent usedsuch as lactose in the initial steps in the formulation process. In theprocess of the present invention lactose is not used. Rather, thecombination of the active principle, diluent and alkali metalalkylsulfate act as the wetting agent in the process.

In an aspect the present invention also provides a method for preparinga mucosal bioadhesive slow release carrier comprising:

-   a) granulating a mixture of at least one active principle with an    alkali metal alkylsulfate, a diluent and a binding agent;-   b) blending said granulated mixture with at least one bioadhesive    polymer, at least one sustained release polymer and at least one    compression agent; and-   c) compressing the blended mixture obtained in b).

In another aspect, the present invention also relates to a method ofpreparing a bioadhesive carrier, the method comprising:

-   a) mixing at least one active principle with an alkali metal    alkylsulfate and a diluent to form a mixture;-   b) wetting said mixture with a binding agent;-   c) drying and calibrating said mixture;-   d) granulating said mixture to form primary granules;-   e) blending said primary granules with at least one bioadhesive    polymer and at least one sustained release polymer and at least one    compression agent; and-   f) compressing the blended mixture obtained in e).

More specifically, the active principle, the diluent and the alkalimetal alkylsulfate are first individually weighed, sieved and premixedin a blender. The binding agent is weighed and solubilized usingpurified water. The solubilized binding agent is then added to themixture containing the active ingredient and stirred form a wetgranulation. The mixture is granulated using a suitable pharmaceuticalmixer or granulator such as a planetary mixer or a high sear mixer thendried and calibrated.

The bioadhesive polymer, the sustained release polymer and compressionexcipients are then weighed and sieved. These ingredients were thenadded to the primary granulated mixture to form a final blendingmixture, which was then further compressed using a suitable tablet presssuch as a rotative press.

The active principle that can be used in the method of the presentinvention are described above, as well as the particular diluents,binding agents, alkali metal alkylsulfates, bioadhesive polymers andsustained release polymers used in the present method.

In another embodiment the present invention provides a method ofpreparing a bioadhesive carrier, the method comprising:

-   a) mixing at least one active principle selected from: an antiviral,    an analgesic, an anti-inflammatory, an antibiotic, an antiseptic, an    antiemetic and mixtures thereof with 1 to 10% by weight of an alkali    metal alkylsulfate and 1 to 75% by weight of a diluent;-   b) wetting said mixture with 0.5 to 5% by weight binding agent that    has been solubilized;-   c) drying and calibrating said mixture;-   d) granulating said mixture to form primary granules;-   e) blending said primary granules with 5 to 80% by weight of at    least one bioadhesive polymer selected from the group of natural    polymers such as polysaccharides or natural proteins from animal    origin or vegetable origin or synthetic polymers, and mixtures    thereof and 5% to 80% by weight of at least one polymer that    provides a sustained release of the active principle and at least    one compression agent; and-   f) compressing the blended mixture obtained in e).

In yet another aspect the present invention relates to the use of themucosal bioadhesive slow release carrier according to the presentinvention for the manufacture of a medicament to treat mucosal diseases.

In this respect the mucosal diseases can be buccal diseases includingherpes simplex virus 1 (HSV-1), herpes simplex virus (HSV-2), oralmucositis, oral Candidiasis, oral hairy leukoplakia, oral ulcers,salivary gland disturbance, altered oral flora (decreased bacterialflora), taste dysfunction, periodontitis, xerostomia, gastrointestinalmucositis causing secondary changes in oral status includinginflammation, hygiene and dietary intact and oral pain. These diseasescan be treated with at least one active principle or at least twodifferent active principles.

In yet another aspect of the present invention, the mucosal diseases canbe genital diseases including herpes simplex virus 2 (HSV-2), herpessimplex virus 1 (HSV-1) or human papilloma virus. These diseases can betreated with at least one active principle or at least two differentactive principles.

In yet another aspect the present invention relates to the use of themucosal bioadhesive slow release carrier according to the invention forthe manufacture of a medicament to treat herpes simplex virus 1 (HSV-1),herpes simplex virus 2 (HSV-2) Epstein-Barr virus, human papillomavirus, cytomegalovirus, variacella-Zoster virus, Kaposi's sarcoma due tohuman herpes V8 and genital warts due to human papilloma virus.

In another aspect the present invention provides a method of deliveringat least one active principle to a mammal in need of said activeprinciple comprising administering the bioadhesive slow release carrierof the present invention, which is described in detail above.

In yet another aspect, the present invention provides a method oftreating a mucosal disease in a mammal in need of such treatment, saidmethod comprising administering the bioadhesive slow release carrier ofthe present invention, which is described in detail above. The mucosaldiseases are described above.

A number of embodiments of the invention have been described.Nevertheless, it will be understood that various modifications may bemade without departing from the spirit and scope of the invention.

EXAMPLES Example 1 Preparation of the Bioadhesive Slow Release Carrierof the Present Invention

100 mg of acyclovir, 15% by weight microcrystalline cellulose and 45% byweight of sodium lauryl sulfate were weighed and sieved with a 0.7 to 2mm sieve before premixing in a blender to provide the “initial mix.”

At the same time, 0.4% by weight polyvinylpyrrolidone was dissolved inpurified water. The resulting solution was added to the initial mix andfurther stirred. The wetted mixture was then granulated using apharmaceutical mixer or granulator such as a planetary mixer or highsear mixer and dried and then calibrated to 500 μm, The resultingpellets formed the “primary granules.”

20% milk concentrate protein, 15% hypromellose, 1% magnesium stearateand 0.4% of colloidal silica were weighed and sieved using a 500 μmsieve. These ingredients were then added to the primary granulation toform the “final blending” mixture. The final blending mixture was thencompressed using a tablet press such as a rotative press to produce thecompressed carriers according to the invention.

The size of the tablets was about 10 mm in diameter. The dimension waschosen to be comfortable in the canine fossa.

The above-described method was suitable for the production of compressedcarrier batches ranging from 2 to 23 kg.

Example 2 Particle Size Distribution of the Primary Granules

The primary granules obtained from the procedure in Example 1, aftergranulating, drying and calibrating, were then evaluated by sieveanalysis based on the procedure described in the European Pharmacopoeia.Also an analysis was undertaken to determine the content of acyclovir inthe different fractions of the granulations or in the whole granule. Theacyclovir content in the granule was assayed using phosphate buffer atpH 6. Two different formulations were compared. The first formulationcorresponded to those obtained in Example 1 of the present invention,while the “control formulation” was that disclosed in U.S. Pat. No.6,916,485, to obtain the “primary grain” set forth in FIG. 1 therein.

The results are presented in FIG. 2. When granulations were preparedaccording to the formulation described in U.S. Pat. No. 6,916,485 (whitebars), the size distribution of the granules reveals a strongheterogeneity, with the presence of two predominant extreme populationswith a granule diameter of greater than 1000 μm or less than 125 μm,respectively. It further appeared that the acyclovir content of thegranules having a size distribution of less than 125 μm granules isunder-dosed.

To the contrary, when the granules were prepared according to the methodof the present invention (dark bars in FIG. 2), the predominant fractionof granules had a diameter of less than 125 μm. The size distribution ishomogeneous with that of the excipients that were added in the externalphase. Further, the flow properties of the granules made according toExample 1 above were totally compatible with the compression step, andthe final blending possessed a very good compression ability. Finally,the resulting granules of the present invention contained 100% of thedesired acyclovir content, as well as the corresponding compressedcarrier, thereby demonstrating the homogeneity of the blending and thereliability of the fabrication process.

Example 3 In vitro Evaluation of an Acyclovir Bioadhesive Slow ReleaseCarrier

The bioadhesive slow release carriers obtained by the process describedin Example 1 were tested for acyclovir release through a dissolutionmethod. The test was conducted according to the current dissolutiontesting described in U.S. Pharmacopoeia, 23^(rd) edition, Chapter 711(Dissolution) pages 1791-1793. More specifically, sample vessels weresubmerged in a water bath at 37° C., in a suitable dissolution medium ofphosphate buffer at a pH of 6 and the content of the vessels wereagitated using a “rotating basket” attached to a shaft that is alsoattached to another shaft. The solid bioadhesive slow release carriersof the present invention were placed in the medium filled vessel at timezero. The water bath was maintained at 37° C. throughout the experiment,as well as the mixing speed of 60 rpm. 1 ml aliquots were taken from thevessels every hour for the first eight hours, then at 10, 11, 12, 15 and24 hours and the amount of acyclovir released in the dissolution mediumwas measured by HPLC.

The resulting dissolution profile is set forth in FIG. 3. Asdemonstrated in this graph, acyclovir released from the bioadhesive slowrelease carrier of the present invention is progressive and sustainedduring 24 hours, with a predominant amount of acyclovir (80%) releasedafter 10 hours.

Example 4 Pharmacokinetics of the Acyclovir Bioadhesive Slow ReleaseCarrier

The main goal of this pharmacokinetic study was to evaluate the systemicpassage of the acyclovir following the application of the bioadhesiveslow release carrier at the level of the canine fossa (upper gingiva) inhealthy volunteers. Additional goals were to evaluate the loco-regionalconcentrations of acyclovir in the saliva, which represents a virusreservoir site, and at the labial level, which constitutes theexpression site for an herpes simplex 1 infection.

In order to evaluate the absorption level of acyclovir through the newmode of administration of the present invention, data was obtained withthe bioadhesive slow release carrier of the present invention andcompared to oral administration of 200 mg acyclovir tablets. Further, toevaluate the therapeutic potential of the new bioadhesive slow releasecarriers of the present invention, plasma and loco-regionalconcentrations were compared to the minimal inhibitory concentration(MIC) of acyclovir towards HSV-1 virus, which is 22.5 ng/ml.

The study was undertaken using 12 healthy volunteers and was amonocentric, randomized, cross-over and open evaluation.

Two acyclovir bioadhesive slow release carriers synthesized according toExample 1 were tested, containing either 50 mg or 100 mg of acyclovir.

Plasma, salivary and labial (lip) samples were taken prior to theadministration of the treatment, and then regularly at 24 hours, 36hours and 48 hours after administration. Labial sampling wasaccomplished by utilizing a stripping method; i.e., an adhesive disk wasused to collect the superficial cell layers of the lip. To avoid lipcontamination with saliva, labial sampling was performed prior to salivasampling after the lips were carefully wiped.

The acyclovir was then extracted and measured by HPLC. Thequantification limit was set at 10 ng/ml for plasma and saliva samples,and at 6.5 ng/cm² for labial samples.

Example 5 Evaluation of the Acyclovir Systemic Transfer

The plasma concentration profiles are presented in FIG. 4.

The control tablet corresponding to the orally administered acyclovirexhibits an immediate-release profile, characterized by a rapidabsorption phase, with a maximum concentration of 254 ng/ml at 1.5hours. As seen in FIG. 4, the control tablet allows the plasmaconcentration of acyclovir to remain higher than the minimal inhibitoryconcentration (MIC) during 14 hours.

To the contrary, the acyclovir bioadhesive slow release carriers of thepresent invention exhibit a sustained-release profile with a 6 hourdelay in the absorption of the acyclovir, and a maximum concentration of45.9 μg/ml at 12 hours. After an increasing absorption phase, meanplasma concentrations remain constant between 30.9 and 37.8 ng/ml for an8 hour period. Additionally, the plasma concentration of acyclovir isnow maintained above the minimal inhibitory concentration (MIC) during16 hours. From the control tablet results, the relative bioavailabilityof the acyclovir released in the bioadhesive carrier could becalculated. This bioavailability was 35%, but for a dose that was twotimes less than the control. When calculated with the same dosage as thecontrol, the bioavailability is 70%.

This example proves that the systemic transfer of acyclovir may occur bythe transmucosal route, following the impregnation of the strongvascular oral mucosis or by oral route, following the swallowing ofsaliva enriched in solubilized acyclovir.

Example 6 Evaluation of the Acyclovir Saliva Concentration

FIG. 5 illustrates the acyclovir salivary concentration profilesobtained either with the control tablet or with the bioadhesive slowrelease carrier according to the present invention. As seen in FIG. 5,when the control tablet is administered, the acyclovir appeared in thesaliva around 30 minutes after administration, with a peak correspondingto a maximal concentration of 112 ng/ml. The acyclovir salivaconcentration remains higher than the minimal inhibitory concentration(MIC) for 4 hours, but decreases quickly after the peak to becomeundetectable 10 hours after administration.

To the contrary, the bioadhesive slow release carrier of the presentinvention had very high levels of acyclovir saliva concentrations, evenafter the first sample taken at 30 minutes after administration. Forinstance, the saliva concentration of acyclovir was estimated at 6.8μg/ml after administration of the 50 mg bioadhesive slow releasecarrier, and at 20 μg/ml after administration of the 100 mg bioadhesiveslow release carrier after 30 minutes.

The acyclovir concentrations remained very high during 24 hours to 36hours, with maximum concentration values of 387 μg/ml and 471 μg/mlrespectively for the 50 and 100 mg bioadhesive slow release carriers.This demonstrated that the bioadhesive slow release carriers of thepresent invention permit the liberation of acyclovir very quickly (30minutes) and for a long duration of time (36 hours) at the site of theherpes simplex virus-1. These concentrations are much more higher thanthe acyclovir minimal inhibitory concentration (MIC) required to treatherpes simplex virus-1, since they are respectively 17,000 (for the 50mg carrier) to 21,000 (for the 100 mg carrier) times greater than therequired minimal inhibitory concentration (MIC).

Furthermore, the bioadhesive carrier of the invention reaches a AUC/MIC(area under the curve/minimal inhibitory concentration) ratio of 103,000to 216,000 in local saliva, while the instant release carrier onlyprovides an AUC/MIC ratio of 8. These exceptionally high ratiosdemonstrate the very high presence of acyclovir in the saliva, which isat a close proximity to the infection site and therefore favoursconsiderably its local efficiency.

Taken together, these results demonstrate that the acyclovir bioadhesiveslow release carrier of the invention favours a very early and sustainedrelease of the acyclovir in the virus reservoir site. Furthermore, thevery important amounts of acyclovir in saliva may contribute to limitintra and inter-individual contamination, since it is well known thatthe virus reservoir potential of saliva plays a key role in the viralspread.

Example 7 Evaluation of the Acyclovir Labial Concentration

As disclosed in FIG. 6, acyclovir is not detectable in the labialsamples after administration of the control tablet.

To the contrary, when the acyclovir bioadhesive slow release carrier ofthe present invention was administered, the amount of acyclovir measuredon the lips reached concentrations as high as 1 mg/ml. This strongpresence of acyclovir on labial sites is maintained during at least 24h.

The results presented herein thus demonstrate that the carriersaccording to the invention favour the persistence of very high amountsof acyclovir on the lips i.e., at the expression site of the disease.This implies an increased pressure exerted against the HSV-1 virus,especially at the epidermic level, and suggests a greater efficiency ofacyclovir against herpes labialis.

Example 8 Preparation of the Bioadhesive Slow Release Carrier withDifferent Bioadhesive Polymer

50 mg of acyclovir, 15% by weight microcrystalline cellulose and 4.5% byweight of sodium lauryl sulfate were weighed and sieved with a 0.7 to 2mm sieve before premixing in a blender to provide the “initial mix.”

At the same time, 0.4% by weight polyvinylpyrrolidone was dissolvedpurified water. The resulting solution was added to the initial mix andfurther stirred. The wetted mixture was then granulated using apharmaceutical mixer or granulator such as a planetary mixer or highsear mixer and dried and then calibrated to 500 μm. The resultingpellets formed the “primary granules.”

20% of mucoadhesive agent (milk concentrate protein or pea protein orcarbopol 974 or chitosan), 15% hypromellose, 1% magnesium stearate and0.4% of colloidal silica were weighed and sieved using a 500 μm sieve.These ingredients were then added to the primary granulation to form the“final blending” mixture. The final blending mixture was then compressedusing a tablet press such as a rotative press to produce the compressedcarriers according to the invention.

The size of the tablets was about 8 mm in diameter. The dimension waschosen to be comfortable in the canine fossa.

The above-described method was suitable for the production of compressedcarrier batches ranging from 2 to 23 kg.

Example 9 In vitro Evaluation of the Adhesion-Ability of the AcyclovirBioadhesive Slow Release Carrier

The adhesion ability of the bioadhesive slow release carrier accordingto the example 8 was measured using a texturometer equipment. Theacyclovir carrier was fixed on a plastic probe. The probe came down tothe immerged stainless bench, stopped, and then came up.

Adhesion ability was expressed as the “adhesion force” (g), the maximumforce needed to separate the tablet, fixed on the probe, from thestainless central parts.

The results of the adhesion force for different mucoadhesive agent arepresented in FIG. 7.

The results have shown that the different mucoadhesive agents are ableto confer similar adhesive properties.

Example 10 In vivo Evaluation of the Adhesion-Lasting of the AcyclovirBioadhesive Slow Release Carrier

To evaluate the adhesion time of the bioadhesive slow release carrieraccording to the present invention, this acyclovir carrier was appliedon 12 healthy volunteers inside the upper lip. The presence of thecarrier was checked at various times until 48 hours. The volunteers werechecked on a regular basis for the loss of their carrier just until 24hours after application. The results of this evaluation are disclosed inthe following Table 1.

TABLE 1 ADHESION TIME (hours) 50 mg carrier 100 mg carrier Median 14 18Minimum 6 10 Maximum 18 24These results demonstrate that the carrier adhesion is completelycompatible with a “once-daily” form of administration. Indeed, as longas the carrier remains at the application site, acyclovir is locallyreleased in close proximity to the aimed infection site. Therefore, theacyclovir bioadhesive slow release carrier obtained with the methoddisclosed in Example 1 now renders possible the “once-daily” localadministration of acyclovir, while achieving efficient loco-regionalconcentrations of the active principle with respect to the MIC.

Example 11 Preparation of the Bioadhesive Slow Release Carrier withFentanyl

2,000 μg of fentanyl citrate, 30% by weight microcrystalline celluloseand 2% by weight of sodium lauryl sulfate are weighed and sieved using a0.7 to 2 mm sieve, before premixing in a blender to provide the “initialmix.”

At the same time, 0.5% by weight polyvinylpyrrolidone is dissolved inpurified water. The resulting solution is added to the initial mix andfurther stirred. The wetted mixture is then granulated using apharmaceutical mixer or granulator such as a planetart mixer or highsearmixer, and dried and then calibrated to 500 μm. The resulting pelletsform the “primary granulation.”

30% milk concentrate protein, 20% hypromellose, 0.2% magnesium stearateand 0.2% of colloidal silica are weighed and sieved using a 500 μmsieve. These ingredients are then added to the primary granulation toform the “final blending” mixture. The final blending mixture is thencompressed using a tablet press such as a rotative press to produce thecompressed carriers according to the invention.

The same procedure as above is followed to prepare a 800 μg dose offentanyl.

Example 12 In vivo Evaluation of the Adhesion-Lasting of the FentanylBioadhesive Slow Release Carrier

To evaluate the adhesion time of the bioadhesive slow release carrieraccording to the present invention, this fentanyl carrier will beapplied on 12 healthy volunteers inside the upper lip following the sameprocedure as in Example 8. The results of this evaluation are set forthin the following Table 2.

TABLE 1 ADHESION TIME (hours) 800 μg carrier 2,000 μg carrier Median 2024 Minimum 17 19 Maximum 36 38

Example 13 Preparation of the Bioadhesive Slow Release Carrier UsingThree Active Principles

Following Example 1, the same bioadhesive slow release carrier isprepared using 70 mg acyclovir, 80 μg fentanyl and 5% by weightpilocarpine. To evaluate the adhesion of this carrier, the sameprocedure is undertaken as in Example 8. The resulting adhesion time issimilar to that in Example 10.

While the invention has been described in terms of various preferredembodiments, the skilled artisan will appreciate that variousmodifications, substitutions, omissions and changes may be made withoutdeparting from the scope thereof. Accordingly, it is intended that thescope of the present invention be limited by the scope of the followingclaims, including equivalents thereof.

1-33. (canceled)
 34. A method for preparing a mucosal bioadhesive slowrelease carrier formulation comprising: (a) mixing at least one activeprinciple with an alkali metal alkylsulfate and at least one diluent,thereby producing a mixture; (b) wetting said mixture of (a) with abinding agent; (c) drying and calibrating said mixture of (b); (d)granulating said mixture of (c) to form primary granules; (e) blendingsaid primary granules with at least one bioadhesive polymer and at leastone sustained release polymer and at least one compression agent; and(f) compressing said blended primary granules of (e).
 35. The methodaccording to claim 34, wherein said at least one active principle is awater-soluble active principle and wherein said at least one diluent isan insoluble diluent.
 36. The method according to claim 34, wherein saidat least one active principle is an insoluble active principle andwherein said at least one diluent is a water-soluble diluent.
 37. Themethod according to claim 34, wherein the binding agent ispolyvinylpyrrolidone.
 38. The method according to claim 34, wherein theat least one bioadhesive polymer comprises natural proteins selectedfrom the group of natural milk proteins, carbomer, alginate, chitosan,xanthum gum, hydroxypropyl cellulose, polyvinylalcohol, carboxymethylcellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose,sodium-hyaluronate, acrylic polymers and mixtures thereof.
 39. Themethod according to claim 34, wherein the at least one sustained releasepolymer is a cellulose polymer or a derivative of a cellulose polymer.40. The method according to claim 39, wherein said cellulose polymer ishypromellose.
 41. The method according to claim 34, wherein said atleast one active principle is selected from: an antiviral, anantifungal, an analgesic, an anaesthetic, an antalgic, an antiemetic, asalivation agent, an antiseptic, an anti-inflammatory, an antibiotic,and mixtures thereof.
 42. The method according to claim 41, wherein atleast one active principle is an antiviral.
 43. The method according toclaim 42, wherein at least one active principle is acyclovir.
 44. Themethod according to claim 41, wherein a second active principle is mixedwith said at least one active principle in step (a).
 45. The methodaccording to claim 44, wherein said second active principle is selectedfrom: an antiviral; an antifungal, an analgesic, an anaesthetic, anantalgic, an antiemetic, a salivation agent, an antiseptic, ananti-inflammatory, an antibiotic and mixtures thereof.